THE AUTHENTIC LIVE INFLUENZA CELL–BASED VACCINE AND ITS IMITATIONS



Cite item

Full Text

Abstract

Abstract

The problem of transferring the technology of influenza vaccine production from developing chicken embryos to mammalian cell culture has been discussed for many years. The technologies being developed for the production of cell–based vaccines rely on two promising substrates – continuous Vero and MDCK cell lines, which effectively support the replication of influenza viruses of various subtypes. In 2018, the WHO issued the first recommendations on the composition of influenza vaccines produced in mammalian cell culture. Since then, the WHO has issued separate recommendations for egg–based and cell–based vaccines for the upcoming epidemic season. The cell–based influenza vaccine has a number of undeniable advantages: the possibility of mass production of the vaccine preparation, which is particularly important during a pandemic, and the lack of an allergenic factor such as egg white in the vaccine. It is also believed that conventional egg–based influenza vaccines may be less effective than cell–based vaccines due to acquired adaptive “egg” mutations. All of the above suggests that the development of appropriate cellular systems highly sensitive to currently circulating influenza virus strains and capable of ensuring the accumulation of large amounts of viral biomass is of considerable practical interest. If we compare two conventional influenza vaccines, inactivated and live, the latter has a number of advantages, such as a non–injection route of administration, a broader spectrum of protection, high yield, low cost, simplicity of the production process, etc. If we add to this a new – cellular – substrate for the production and accumulation of viral biomass, we have the prospect of developing a vaccine preparation with virtually no drawbacks. Despite the obvious advantages of cell culture as a substrate for influenza vaccine production, some influenza vaccines, including live attenuated cold–adapted influenza vaccine, are still produced in the developing chicken embryos. Therefore, we considered it appropriate to collect the available scientific literature on the development of approaches for the production of a live influenza cold–adapted cell–based vaccine.

About the authors

Irina Vasilievna Kiseleva

Institute of Experimental Medicine, Saint Petersburg, Russia

Email: irina.v.kiseleva@mail.ru
ORCID iD: 0000-0002-3892-9873
SPIN-code: 7857-7306
Scopus Author ID: 7102041346
ResearcherId: E-6555-2014

Head of the Laboratory of General Virology

Россия, 12 Acad. Pavlov Street, S. Petersburg, 197022, Russia

Natalie Valentinovna Larionova

Institute of Experimental Medicine, Saint Petersburg, Russia

Author for correspondence.
Email: nvlarionova@mail.ru
ORCID iD: 0000-0003-1171-3383
SPIN-code: 4709-5010
Scopus Author ID: 23497140200
ResearcherId: J-5004-2018

Doctor of Biological Sciences, Leading Research Associate at the Laboratory of General Virology

Россия, 12 Acad. Pavlov Street, S. Petersburg, 197022, Russia

References

  1. Киселева И.В., Исакова И.Н., Ларионова Н.В., Олейник Е.С., Руденко Л.Г. Эффективность получения реассортантов между эпидемическими и холодоадаптированными вирусами гриппа в развивающихся куриных эмбрионах и в культуре клеток MDCK // ЖМЭИ. 2007. № 6. С. 40–45. [Kiseleva I.V., Isakova I.N., Larionova N.V., Oleĭnik E.S., Rudenko L.G. Efficacy of production of reassortant of epidemic strains and cold-adapted influenza viruses in chicken embryo and MDCK cells. Zh. Mikrobiol. Epidemiol. Immunobiol., 2007, 6:40-45. (in Russ.)] PMID: 18283733
  2. Ларионова Н.В., Киселева И.В., Александрова Г.И., Руденко Л.Г. Штамм вируса гриппа А/17/Калифорния/2009/38 (H1N1) для производства живой гриппозной интраназальной вакцины для взрослых и детей. Патент РФ №2315101 от 16.09.2009. Опубл. БИ 2011. №7. [A/17/California/2009/38 (H1N1) influenza virus strain for the production of live influenza intranasal vaccine for adults and children. Patent of the Russian Federation No. 2315101. Published 2011 in Invention Bulletin no. 7. Effective date for property rights 16.09.2009 (in Russ.)] https://www1.fips.ru/registers-doc-view/fips_servlet?DB=RUPAT&DocNumber=2413765&TypeFile=html
  3. Лю Д., Томпсон М., Маранга Л.Ж., Катаниаг Ф., Сюй С.С. Способы культивирования клеток, размножения и очистки вирусов. Патент РФ №2547587 от 24.09.2009. Опубл. БИ 2015, № 10 [Lu D.L., Tompson M., Maranga L.Zh., Kataniag F., Xu S.S. Methods for cell culture, virus replication and purification. Patent of the Russian Federation No. 2547587. Published in Invention Bulletin, 2015, no 10. Effective date for property rights 24.09.2009 (in Russ.)] https://patentimages.storage.googleapis.com/a7/89/86/417cb8e9b1cce6/RU2547587C2.pdf
  4. Нечаева Е.А., Сенькина Т.А., Радаева И.Ф., Вараксин Н.А., Рябичева Т.Г., Жилина Н.В., Думченко Н.Б., Руденко Л.Г., Киселева И.В., Исакова–Сивак И.Н. Способ получения микрокапсулированной формы живой культуральной вакцины против сезонного и пандемического гриппа для интраназального применения. Патент №2617051 от 04.05.2016. Опубл. БИ 2017, №11. [Nechaeva E.A., Senkina T.A., Radaeva I.F., Varaksin N.A., Ryabicheva T.G., Zhilina N.V., Dumchenko N.B., Rudenko L.G., Kiseleva I.V., Isakova–Sivak I.N. Method for obtaining a microencapsulated form of a live culture vaccine against seasonal and pandemic influenza for intranasal use. Patent of the Russian Federation No. 2617051. Published in Invention Bulletin, 2017, no. 11. Effective date for property rights 04.05.2016. (in Russ.)] https://www1.fips.ru/ofpstorage/Doc/IZPM/RUNWC1/000/000/002/617/051/%D0%98%D0%97-02617051-00001/document.pdf
  5. Нечаева Е.А., Радаева И.Ф., Сенькина Т.Ю., Герасименко Н.Б., Богрянцева М.П., Костылева Р.Н., Жилина Н.В., Свириденко Н.М., Зубарева К.Э., Вараксин Н.А., Рябичева Т.Г., Киселева И.В., Ларионова Н.В., Руденко Л.Г. Разработка опытно–промышленной технологии производства живой культуральной вакцины против пандемического гриппа. Биотехнология. 2013. № 6. С. 23–34. [Nechaeva E.A., Radaeva I.F., Sen’kina T.Yu., B gerasimenko N., Bogryantseva M.P., Kostyleva R.N., Zhilina N.V., Sviridenko T.M., Zubareva K.E., Varaksin N.A., Ryabicheva T.G., Kiseleva I.V., Larionova N.V., Rudenko L.G. Development of pilot technology for cell-based anti-influenza live attenuated pandemic vaccine manufacturing. Biotechnology in Russia. 2013, no. 6, pp. 23–34. (in Russ.)] https://elibrary.ru/download/elibrary_23515897_84010445.pdf
  6. Райтер М., Мундт В. Способ крупномасштабного производства вирусного антигена. Патент РФ №2314344 от 10.12.2002. Опубл. БИ 10.01.2008, № 1. [Rajter M., Mundt V. Method for large-scale production of viral antigen. Patent of the Russian Federation No. 2314344 dated 10.12.2002. Published in Invention Bulletin, 2008, No 1. Effective date for property rights 10.12.2002. (in Russ.)] https://patentimages.storage.googleapis.com/df/59/44/4a5e02cfdf5dd6/RU2314344C2.pdf
  7. Уесмоен Т.Л., Гао П., Эдди Б.А., Абдельмагид О.Ю. Способ репликации вируса гриппа в культуре. Патент РФ №2491339 от 14.12.2007. Опубл. БИ 20.01.2011, № 2. [Uesmoen T.L., Gao P., Ehddi B.A., Abdel’magid O.J. Method of replication of influenza virus in culture. Patent of the Russian Federation No. 2491339 dated 14.12.2007. Published in Invention Bulletin, 2011, No 2. Effective date for property rights 14.12.2007. (in Russ.)] https://patentimages.storage.googleapis.com/ba/39/39/2895a7916bb5b8/RU2491339C2.pdf
  8. Aldeán Á.J., Salamanca I., Ocaña D., Barranco J.L., Walter S. Effectiveness of cell culture–based influenza vaccines compared with egg–based vaccines: What does the literature say? Rev. Esp. Quimioter., 2022, vol. 35, no. 3, pp. 241–248. – doi: 10.37201/req/117.2021
  9. Alymova I.V., Kodihalli S., Govorkova E.A., Fanget B., Gerdil C., Webster R.G. Immunogenicity and protective efficacy in mice of influenza B virus vaccines grown in mammalian cells or embryonated chicken eggs. J. Virol., 1998, vol. 72, no. 5, pp. 4472–4477. – doi: 10.1128/JVI.72.5.4472-4477.1998
  10. Andrianov, A. K., Chen, J. Preparation of ionically cross–linked polyphosphazene microspheresy by coacervation. US Patent No. 5807757. Effective date for property rights 02.07.1996. Published 15.09.1998. – https://patentimages.storage.googleapis.com/07/3b/a5/8f03b042ac2cab/US5807757.pdf
  11. Audsley J.M., Tannock G.A. Cell–based influenza vaccines: progress to date. Drugs, 2008, vol. 68, no. 11, pp. 1483–1491. – doi: 10.2165/00003495-200868110-00002
  12. Bilsel P., Kawaoka Y. Cell-based systems for producing influenza vaccines. International Patent No. 2351300. Effective date for property rights 11.06.2008. Published 09.06.2009. – https://patentimages.storage.googleapis.com/37/4f/9e/fb6b8b9029071a/WO2009152181A1.pdf
  13. Boikos C., Sylvester G.C., Sampalis, J.S., Mansi J.A. Relative Effectiveness of the Cell–Cultured Quadrivalent Influenza Vaccine Compared to Standard, Egg–derived Quadrivalent Influenza Vaccines in Preventing Influenza–like Illness in 2017–2018. Clin. Infect. Dis., 2020, vol. 68, no. 11, pp. e665–e671. – doi: 10.1093/cid/ciaa371
  14. CDC. Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices. United States, 2013–2014. MMWR Recomm. Rep., 2013, 62, pp. 1–43. – PMID: 24048214
  15. CDC. 2025. Cell–based flu vaccines. [Online]. – https://www.cdc.gov/flu/vaccine-types/cell-based.html
  16. Cheng X., Zengel J.R., Suguitan A.L. Jr., Xu Q., Wang W., Lin J., Jin H. Evaluation of the humoral and cellular immune responses elicited by the live attenuated and inactivated influenza vaccines and their roles in heterologous protection in ferrets. J. Infect. Dis., 2013, vol. 208, no. 4, pp. 594–602. – doi: 10.1093/infdis/jit207
  17. FDA. 20 November 2012. Approval Letter – Flucelvax. [Online]. – https://web.archive.org/web/20160310193425/http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm328684.htm
  18. Feng S.Z., Jiao P.R., Qi W.B., Fan H.Y., Liao M. Development and strategies of cell–culture technology for influenza vaccine. Appl. Microbiol. Biotechnol., 2011, vol. 89, no. 4, pp. 893–902. – doi: 10.1007/s00253-010-2973-9
  19. Frech C., Lubben H., Vorlop J., Gregersen J–P. Procedure for the industrial-scale preparation of vaccines. European Patent No. 2351300. Effective date for property rights 12.09.2001. Published 02.02.2011. – https://patentimages.storage.googleapis.com/d8/48/2d/ddb1caaa817bcb/ES2351300T3.pdf
  20. Genzel Y., Dietzsch C., Rapp E., Schwarzer J, Reichl U. MDCK and Vero cells for influenza virus vaccine production: a one–to–one comparison up to lab–scale bioreactor cultivation. Appl. Microbiol. Biotechnol., 2010, vol. 88, no. 2, pp. 461–475. – doi: 10.1007/s00253-010-2742-9
  21. Heldens J., Hulskotte E., Voeten T., Breedveld B., Verweij P., Van Duijnhoven W., Rudenko L., Van Damme P., Van Den Bosch H. Safety and immunogenicity in man of a cell culture derived trivalent live attenuated seasonal influenza vaccine: a Phase I dose escalating study in healthy volunteers. Vaccine, 2014, vol. 32, no. 39, pp. 5118–5124. – 1. doi: 10.1016/j.vaccine.2014.05.030
  22. Hussain A. I., Cordeiro M., Sevilla E., Liu J. Comparison of egg and high yielding MDCK cell–derived live attenuated influenza virus for commercial production of trivalent influenza vaccine: in vitro cell susceptibility and influenza virus replication kinetics in permissive and semi–permissive cells. Vaccine, 2010, vol. 28, no. 22, pp. 3848–3855. – doi: 10.1016/j.vaccine.2010.03.005
  23. Izurieta H.S., Chillarige Y., Kelman J., Wei Y., Lu Y., Xu W., Lu M., Pratt D., Chu S., Wernecke M., Macurdy T., Forshee R. Relative Effectiveness of Cell–Cultured and Egg–Based Influenza Vaccines Among Elderly Persons in the United States, 2017–2018. J. Infect. Dis., 2019, vol. 220, no. 8, pp. 1255–1264. – doi: 10.1093/infdis/jiy716
  24. Katz J.M., Webster R.G. Efficacy of inactivated influenza A virus (H3N2) vaccines grown in mammalian cells or embryonated eggs. J Infect Dis, 1989, vol. 160, no. 2, pp. 191–198. – doi: 10.1093/infdis/160.2.191
  25. Kiseleva I., Su Q., Toner T.J., Szymkowiak C., Kwan W.S., Rudenko L., Shaw A. R., Youil R. Cell–based assay for the determination of temperature sensitive and cold adapted phenotypes of influenza viruses. J. Virol. Methods, 2004, vol. 116, no. 1, pp. 71–78. – doi: 10.1016/j.jviromet.2003.10.012
  26. Lanthier P.A., Huston G.E., Moquin A., Eaton S.M., Szaba F.M., Kummer L.W., Tighe M.P., Kohlmeier J.E., Blair P.J., Broderick M., Smiley S.T., Haynes L. Live attenuated influenza vaccine (LAIV) impacts innate and adaptive immune responses. Vaccine, 2011, vol. 29, no. 44, pp. 7849–7856. – doi: 10.1128/mbio.01040-13
  27. Lee M.S., Hu A.Y. A cell–based backup to speed up pandemic influenza vaccine production. Trends Microbiol., 2012, vol. 20, no. 3, pp.103–105. – doi: 10.1016/j.tim.2011.12.002
  28. Liu J., Shi X., Schwartz, R., Kemble, G. Use of MDCK cells for production of live attenuated influenza vaccine. Vaccine, 2009, vol. 27, no. 46, pp. 6460–6463. – doi: 10.1016/j.vaccine.2009.06.024
  29. Mahallawi W.H., Zhang Q. Live attenuated influenza vaccine induces broadly cross–reactive mucosal antibody responses to different influenza strains in tonsils. Saudi J. Biol. Sci., 2023, vol. 30, no. 10 , pp. 103809. – doi: 10.1016/j.sjbs.2023.103809
  30. Manini, I., Trombetta, C. M., Lazzeri, G., Pozzi, T., Rossi, S. & Montomoli, E. Egg–independent influenza vaccines and vaccine candidates. Vaccines, 2017, vol. 5, no. 3, pp. 18. – doi: 10.3390/vaccines5030018
  31. Montomoli E., Khadang B., Piccirella S., Trombetta C., Mennitto E., Manini I., Stanzani V., Lapini G. Cell culture–derived influenza vaccines from Vero cells: a new horizon for vaccine production. Expert Rev. Vaccines, 2012, vol. 11, no. 5, pp. 587–594. – doi: 10.1586/erv.12.24
  32. Moro P.L., Winiecki S., Lewis P., Shimabukuro T.T., Cano M. Surveillance of adverse events after the first trivalent inactivated influenza vaccine produced in mammalian cell culture (Flucelvax®) reported to the Vaccine Adverse Event Reporting System (VAERS), United States, 2013–2015. Vaccine, 2015, vol. 33, no. 48, pp. 6684–6688. – doi: 10.1016/j.vaccine.2015.10.084
  33. Morokutti A., Muster T., Ferko B. Intranasal vaccination with a replication–deficient influenza virus induces heterosubtypic neutralising mucosal IgA antibodies in humans. Vaccine, 2014, vol. 32, no. 17, pp. 1897–900. – doi: 10.1016/j.vaccine.2014.02.009
  34. Nechaeva E.A., Ryzhikov A.B., Pyankova O.G., Radaeva I.F., Pyankov O.V., Danilchenko N.V., Agafonov A.P., Kiseleva I.V., Larionova N.V., Rudenko L.G. Study of immunogenicity and protective efficacy of live MDCK–derived pandemic influenza vaccine. Glob. J. Infect. Dis. Clin. Res., 2019, vol. 5, no. 1, pp. 010–015. – doi: 10.17352/2455-5363.000023
  35. Nechaeva E.A., Sen'kina T.Y., Ryzhikov A.B., Radaeva I.F., P'yankova O.G., Danil'chenko N. V., Sviridenko T.M., Bogryantzeva M.P., Gilina N.V., Varaksin N.A., Ryabicheva T.G., Kiseleva I.V., Rudenko L.G. Development of live cultural pandemic influenza vaccine Vector–Flu. BMC Proc., 2011, vol. 5, Suppl 8, p.104. – doi: 10.1186/1753-6561-5-S8-P104
  36. Palker T., Kiseleva I., Johnston K., Su Q., Toner T., Szymkowiak C., Kwan W. S., Rubin B., Petrukhin L., Wlochoski J. , Monteiro J., Kraiouchkine N., Distefano D., Rudenko L., Shaw A., Youil R. Protective efficacy of intranasal cold–adapted influenza A/New Caledonia/20/99 (H1N1) vaccines comprised of egg– or cell culture–derived reassortants. Virus Res., 2004, vol. 105, no. 2, pp. 183–194. – doi: 10.1016/j.virusres.2004.05.009
  37. Robertson J. S., Cook P., Attwell A.M., Williams S.P. Replicative advantage in tissue culture of egg–adapted influenza virus over tissue–culture derived virus: implications for vaccine manufacture. Vaccine, 13, 1995, no. 6, pp. 1583–1588. – doi: 10.1016/0264-410x(95)00085-f
  38. Romanova J., Katinger D., Ferko B., Vcelar B., Sereinig S., Kuznetsov O., Stukova M., Erofeeva M., Kiselev O., Katinger H., Egorov A. Live cold–adapted influenza A vaccine produced in Vero cell line. Virus Res., 2004, vol.103, no. 1-2, pp.187–193. – DOI: 10.1016/j.
  39. Sasaki S., Holmes T.H., Albrecht R.A., García–Sastre A., Dekker C.L., He X.S., Greenberg H.B. Distinct cross–reactive B–cell responses to live attenuated and inactivated influenza vaccines. J. Infect. Dis., 2014, vol. 210, no. 6, pp. 865–874. – doi: 10.1093/infdis/jiu190
  40. Shcherbik S., Pearce N., Kiseleva I., Larionova N., Rudenko L., Xu X., Wentworth D. E. Bousse T. Implementation of new approaches for generating conventional reassortants for live attenuated influenza vaccine based on Russian master donor viruses. J. Virol. Methods, 2016, vol. 227, pp. 33–39. – doi: 10.1016/j.jviromet.2015.10.009
  41. Tapia F., Vazquez–Ramirez D., Genzel Y., Reichl U. Bioreactors for high cell density and continuous multi–stage cultivations: options for process intensification in cell culture–based viral vaccine production. Appl. Microbiol. Biotechnol., 2016, vol. 100, pp. 2121–2132. – 2. doi: 10.1007/s00253-015-7267-9
  42. Tree J.A., Richardson C., Fooks A.R., Clegg J.C., Looby D. 2001. Comparison of large–scale mammalian cell culture systems with egg culture for the production of influenza virus A vaccine strains. Vaccine, 19, 3444–3450. – doi: 10.1016/s0264-410x(01)00053-6
  43. Tsai T.F., Heidi T. Making influenza virus vaccines without using eggs. Patent of the USA No. US 2016/0193321 A1. Effective date for property rights 05.11.2015. Published 07.07.2016. – https://patentimages.storage.googleapis.com/d8/48/2d/ddb1caaa817bcb/ES2351300T3.pdf
  44. Wacheck V., Egorov A., Groiss F., Pfeiffer A., Fuereder T., Hoeflmayer D., Kundi M., Popow–Kraupp T., Redlberger–Fritz M., Mueller C. A., Cinatl J., Michaelis M., Geiler J., Bergmann M., Romanova, J., Roethl E., Morokutti A., Wolschek M., Ferko B., Seipelt, J., Dick–Gudenus R., Muster T. A novel type of influenza vaccine: Safety and immunogenicity of replication–deficient influenza virus created by deletion of the interferon antagonist NS1. J. Infect. Dis., 2010, vol. 201, pp. 354–362. – doi: 10.1086/649428
  45. Wareing M.D., Marsh G.A., Tannock G.A. Preparation and characterisation of attenuated cold–adapted influenza A reassortants derived from the A/Leningrad/134/17/57 donor strain. Vaccine, 2002, vol. 20, no. 16, pp. 2082–2090. – doi: 10.1016/s0264-410x(02)00056-7
  46. WHO. 2006. Global action plan to increase vaccine supply for influenza vaccines. [Online]. – http://whqlibdoc.who.int/hq/2006/WHO_IVB_06.13_eng.pdf
  47. WHO. 2018. 27 September 2018. Recommended composition of influenza virus vaccines for use in the 2019 southern hemisphere influenza season [Online]. – https://www.who.int/publications/m/item/recommended-composition-of-influenza-virus-vaccines-for-use-in-the-2019-southern-hemisphere-influenza-season
  48. Youil R., Kiseleva I., Kwan W.S., Szymkowiak C.,Toner T.J., Su Q., Klimov A., Rudenko L. Shaw A.R. Phenotypic and genetic analyses of the heterogeneous population present in the cold–adapted master donor strain: A/Leningrad/134/17/57 (H2N2). Virus Res., 2004a, vol.102, pp. 165–176. – doi: 10.1016/j.virusres.2004.01.026
  49. Youil R., Su Q., Toner T.J., Szymkowiak C., Kwan W.S., Rubin B., Petrukhin L., Kiseleva I., Shaw A.R., Distefano D. Comparative study of influenza virus replication in Vero and MDCK cell lines. J. Virol. Methods, 2004b, vol. 120, pp. 23–31. – doi: 10.1016/j.jviromet.2004.03.011

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) Kiseleva I., Larionova N.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies